PROJECT SUMMARY/ABSTRACT The primary goal of this study is to empower youth in health disparate communities to ameliorate risk for cardiometabolic diseases by evaluating immunoepigenetic-gut microbiome interactions among social networks. Native Hawaiians and Pacific Islanders (NHPIs) experience a disproportionately higher prevalence and earlier onset of Type-2 diabetes mellitus (DM) than other U.S. racial/ethnic groups. These health disparities may result from social network influences on shaping an individual's health behaviors/lifestyle and exposure to an obesogenic environment, as well as from gene-environment interactions underlying DM progression. The detrimental effects of social environments may include an increase in systemic inflammation, a hallmark of cardiometabolic diseases where monocytes of the immune system play a major role. Indeed, we observed an association between neighborhood social environments and inflammation in health disparate populations. Epigenetic mechanisms including DNA methylation regulate transcription of pro-inflammatory genes of monocytes, a key mediator of inflammation, and respond to changes in the gut microbiome associated with lifestyle. Dysbiosis of gut microbiota may be an underlying attribute of inflammatory-related conditions such as DM, which also affects bioavailability of substrates essential for epigenetic processes. Our preliminary data reveal significant genome-wide changes to DNA methylation and gene expression states of pro-inflammatory genes that associated with monocyte inflammatory activity and glycemic control in NHPIs with DM undergoing a lifestyle intervention. Additionally, we observed significant changes to the gut microbiome composition of NHPI youth that associated with reduced risk for DM, which clustered in their social networks. Our data suggest that social environments influence the gut microbiome and the epigenomic landscape of monocytes, which may prime their inflammatory state and contribute to inflammation that consequently lead to disrupted glucose homeostasis. We seek to explore this ?immunoepigenetic-gut microbiome axis? among the social networks of NHPIs at risk for DM. Our unique multidisciplinary team will test the hypotheses that the neighborhood social environment conditions the monocyte epigenomic landscape associated with inflammation, which (1) increases DM risk, (2) propagates among social networks, and (3) is ameliorated by a community-based life development program that impacts the immunoepigenetic-gut microbiome axis. In a two- part study, we will identify an immunoepigenetic signature of DM risk associated with neighborhood level factors using the Multiethnic Cohort (MEC) in a nested case-control study design, and link this with changes to the gut microbiome and subclinical measures of DM in the social networks of NHPI youth over time in a community-based longitudinal study. Responsive to PAR-16-355, this study seeks to advance the science of epigenomics focused on health disparities and expand approaches for understanding epigenetic mechanisms by which social factors lead to biological changes that affect health disparities among NHPIs.